Vascular targets of redox signalling in diabetes mellitus

Abstract

There is overwhelming evidence for an involvement of reactive oxygen species (ROS) in the pathogenesis of diabetes-associated vascular complications. However, neither the exact source of the ROS initiating cascades leading to cell dysfunction in diabetes nor their chemical nature is fully understood. Furthermore, despite our knowledge of the crucial role of ROS in diabetes, little is known about the actual targets and the molecular consequences of the interaction of ROS with cellular signalling pathways.Therefore, we aim to provide an overview of ROS (i. e. O 2 · , NO · , ONOO  and H 2 O 2 ) and their vascular sources in diabetes and to summarise recent knowledge on the mechanisms underlying increased ROS production within the vascular wall. In addition, possible targets of diabetes and ROS within the vasculature are discussed. These include, the effects of ROS on small guanine nucleotide binding proteins, the cytoskeleton, protein kinases (e. g. tyrosine kinases), metalloproteinases, ion homeostasis and transcriptional regulation.Such analysis makes it clear that the generation of ROS could affect a large number of various signalling pathways and proteins. Thus, a better knowledge of the functional diversity and pathological consequences of each individual pathway activated by ROS is essential to understand the mechanisms of diabetesassociated vascular complications. [Diabetologia (2002) 45:476±494]

Intercellular signalling within vascular cells under high D-glucose involves free radical-triggered tyrosine kinase activation

“…Moreover, D-glucose-dependent · O 2 -release from porcine aortic SMC is in line with our previous report that the release of · O 2 -is enhanced in uterine arteries of diabetic patients [6]. The source of SMC · O 2 -and the mechanisms of its release under elevated D-glucose conditions are still a matter of debate, but NAD(P)H oxidase [29,30,31,32,33] and mitochondria [34,35] have been discussed frequently to contribute to increased · O 2 -production in diabetes [7]. Overall, recent literature and our present data suggest that under hyperglycaemic conditions · O 2 -release from SMC is augmented and affects EC function.…”

“…Although these data might be related to this particular type of artery and are in contradiction with reports in murine models [7], it is unclear whether, and if so, how vascular SMC affect EC during diabetes. Such smooth muscle originated modulation of EC function adds to our recent paradigm in which vascular dysfunction in diabetes (and many other diseases) is thought to occur initially in EC that, in turn, affects the vascular SMC [1,8].…”

“…Besides protein kinase C, the modulation of a number of additional signal transduction pathways has been reported in hyperglycaemia [7]. Thus, it seems interesting to assess the endothelial target(s) of smooth muscle-derived factors in hyperglycaemia.…”

Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier

“…14 Prolonged hyperglycemia induces increased levels of ROS such as hydrogen peroxide, hydroxyl radicals and super oxide anions. 19,20 Hyperglycemia and ROS have also been correlated with an elevation of MMP-9 expression and activity that can be attenuated by treatment with antioxidants. 17 It is apparent that in the development of diabetes proteinase expression may be increased by a variety of biochemical mechanisms.…”

Does Bosentan Protect Diabetic Brain Alterations in Rats? The Role of Endothelin‐1 in the Diabetic Brain

“…iNOS production increases within hours in many instances, such as inflammation, and it significantly increases the amount of NO [47,48]. Likewise, it was also shown that high glucose levels significantly increased iNOS activity [49,50]. Additionally, diabetes induced increasing iNOS activity which damaged cellular proteins, inhibited the lipid and protein functions in the neurons and also dis- rupted haemostasis [51].…”